This proposal examines the biochemical basis for a number of human heritable disorders of connective tissues. In particular, patients with a variety of the Ehlers-Danlos syndromes, osteogenesis imperfecta and the Marfan syndrome will be studied. Skin biopsies will be examined for their content of different collagen types and for fibril structure by electron microscopy. Skin fibroblasts will be grown in cell culture and the nature of the procollagens synthesized and the activity of procollagen proteases will be determined. Mutations in collagen genes leading to disturbances in function will be identified by characterization of the structurally defective proteins. Messenger RNA levels will be determined by hybridization with complementary DNA. Recently the collagens have been shown to have functions in addition to those subserved by their structural roles. Thus the extracellular matrix, of which collagen is an important component, plays a crucial role in cell adhesion and migration and therefore in morphogenesis and development. It is of interest that a broad spectrum of dysmorphic changes are seen in the heritable disorders of collagen. In studying the biochemical basis for these disorders we hope to gain a better understanding of the complex mechanisms involved in the regulation of collagen synthesis and in the post-translational processing that is critical to the function of the protein. Although the disorders are relatively rare the metabolic defects are important in that they highlight the functional significance of each collagen type or of each post-translational modification of the collagen molecule.